BackgroundAndrogenetic alopecia (AGA) is a nonscarring progressive miniaturization of the hair follicle with a usually characteristic pattern of distribution in genetically predisposed men and women. Although several previous studies have investigated the association of metabolic syndrome (MS) and cardiovascular risks with AGA, the results have been inconsistent.AimWe attempted to evaluate the possible association between MS and cardiovascular risks with AGA in both male and female patients. This may help to detect whether AGA can be considered as a clue for underlying serious systemic diseases.Patients and methodsA total of 50 patients (38 male and 12 female) and 50 normal sex-matched and age-matched controls were included. Anthropometric measures, blood pressure, fasting glucose, high-density lipoprotein cholesterol, triglycerides, testosterone, sex hormone binding globulin, and serum insulin levels were evaluated. Acute phase reactants (C-reactive protein, fibrinogen, and erythrocyte sedimentation rate) were measured for all participants. The presence of MS, insulin resistance, and cardiovascular risk factors were evaluated.ResultsThere were statistically significant differences with regard to the mean values of waist circumference, BMI, systolic blood pressure, fasting blood sugar, fibrinogen, and Homeostasis Model Assessment of Insulin Resistance in both male and female patients. In contrast, triglycerides, cholesterol, MS, erythrocyte sedimentation rate, and sex hormone binding globulin were significantly elevated in male patients only in relation to their sex-matched controls.ConclusionPatients of both sexes with AGA are more susceptible to have cardiovascular diseases in future compared with people who do not have AGA.

Male pattern baldness, also called androgenetic alopecia (AGA), is the most common cause of hair loss in men. It affects ∼30-40% of adult men and is seen in 80% of men by the age of 80 years. AGA is considered to be a heritable, androgen-dependent condition. It requires adequate circulating androgens and a genetic predisposition. Dihydrotestosterone (DHT) binding to androgenic receptors in hair follicles of the scalp triggers the genes accountable for gradual transformation of large terminal follicles to miniature ones. Such miniaturization is observed on the frontotemporal area and vertex in men, and over the crown in women, as these areas are more sensitive to androgen effects [1],[2].

Cardiovascular diseases (CVD) are a major cause of death and disability worldwide. Advanced obstructive CVD can exist in patients with minimal or no symptoms and can progress rapidly, and so early detection is extremely important [1].

The reason for the association between baldness and CVD is unclear. It has been suggested that classical coronary risk factors (e.g. age, hypertension, dyslipidemia, and smoking) might influence both conditions, and so baldness is a marker of atherosclerosis. In fact, previous studies have demonstrated a positive association between male pattern baldness and insulin resistance [3], metabolic syndrome (MS) [4], and hypertension [5]. It has also been postulated that baldness is linked to CVD by mechanisms such as hyperinsulinemia [6], chronic inflammation, and increased peripheral sensitivity to androgens;

(1) Hyperinsulinemia/insulin resistance is the central factor in MS and it promotes intolerance of carbohydrates and the development of central (abdominal) obesity. Insulin resistance has also been shown to cause vasoconstriction and impair the supply of nutrients to the hair follicles of the scalp, as well as enhancing the influence of DHT on follicular miniaturization [6].

(2) A proinflammatory state could increase the levels of inflammatory cytokines in the arterial walls and hair follicles [7]. High-sensitivity C-reactive protein (CRP) is a marker of inflammation and also a good predictor of future CVD [8], and so chronic inflammation could be related to both coronary heart disease and baldness.

(3) Male pattern baldness might be caused by increased peripheral sensitivity to androgens, as bald men show increased androgen receptors in the scalp [9] and have higher serum levels of both total and free testosterone [10]. Free testosterone is converted to DHT by 5a-reductase, leading to miniaturization of hair follicles. It has been reported that 5a-reductase exists in the blood vessels and the heart, as does the DHT receptor, which is involved in vascular smooth muscle proliferation that represents a fundamental feature of atherosclerosis along with the deposition of lipids [11].

Patients and methods

All patients were informed of the purpose of the study, written consent was obtained from each patient. The study protocol was approved by local ethics committee of Faculty of Medicine, Alexandria University. This case-control study included 100 participants: 50 patients with AGA (38 male and 12 female with a mean age of 44.28 ± 8.60) and 50 age-matched and sex-matched volunteers who served as controls. All patients were recruited from the dermatology outpatient clinic of the Main University Hospital, Faculty of Medicine, Alexandria University.

Exclusion criteria for patients and controls were as follows: presence of other types of alopecia; being recipients of hormone replacement therapy with testosterone; taking contraceptives or undergoing steroid therapy; presence of hyperaldosteronism; or a known cause of hyperandrogenism (e.g. tumor or polycystic ovary syndrome).

History taking was carried out, including family history of CVDs, family history of AGA, smoking (>5 cigarettes/day), sedentariness (physical exercise <30 min/day), diet (sodium intake), and drug intake (antihypertensives, diuretics, hypocholesterolemics, oral antidiabetics, and anti-AGA drugs).

Examinations

The degree of AGA was determined by application of the Ebling scale (I-V) for male patients and the Ludwig scale (II-III) for female patients. The weight, height, and abdominal circumference of participants were measured, and their BMI (kg/m 2 ) was calculated. Systolic and diastolic blood pressure (BP) was measured after a 5-min rest and again 10 min later, recording the mean value.

Prevalence of MS was calculated according to the ATP-III criteria [12]; MS was defined by the presence of three of the following: abdominal circumference greater than 102 cm in men and greater than 88 cm in women; hypertriglyceridemia greater than 150 mg/dl, HDL-C less than 40 mg/dl in men and less than 50 mg/dl in women, BP greater than 130/85 mmHg, or glycemia greater than 110 mg/dl.

Statistical analysis

Data were fed to the computer and analyzed using IBM SPSS software package version 20.0. (18) Qualitative data were described using number and percent. Quantitative data were described using range (minimum and maximum), mean, standard deviation and median. Comparison between different groups regarding categorical variables was tested using Chi-square test. When more than 20% of the cells have expected count less than 5, correction for chi-square was conducted using Monte Carlo or Fisher exact tests. The distributions of quantitative variables were tested for normality using Kolmogorov-Smirnov test, Shapiro-Wilk test and D'Agstino test, if it reveals normal data distribution, parametric tests was applied. If the data were abnormally distributed, non-parametric tests were used. For normally distributed data, comparison between two independent populations was done using independent t-test. For abnormally distributed data, comparison between two independent populations was done using Mann Whitney test.

Results

The age of the patients included in this study was significantly correlated with the severity of AGA, which means there is an increase in AGA severity with aging (P < 0.001* in the male group and P < 0.008* in the female group). There was a statistically significant difference between the patients (both male and female) and their sex-matched control groups as regards waist circumference and BMI, but this was not the same as regards the height or weight [Table 1].

Table 1: Comparison between the two studied groups according to clinical data

The number of diabetic, hypertensive, smoker patients was significantly higher in the patient group in both sexes. This was the same for family history of CVD and AGA.

In the patient group, the severity of AGA based on the Ebling scale was as follows: 5.3% of male patients had stage II AGA, 15.8% had stage III, 15.8% had stage IV, 21.1% had stage V, 26.3% had stage VI, and15.8% had stage VII. Among the female patients, 66.7% had stage I and 33.3% stage II AGA on the Ludwig scale.

ATP-III criteria for MS were met by 21 patients (accounting for 49% of all patients, 47.4% of the male patients, and 25% of the female patients) with AGA versus 10 controls (37.7%) (P ≤ 0.0001); with regard to the male patients this difference was statistically significant [Table 2].

Table 2: Comparison between the two studied groups according to metabolic syndrome in the male and female groups

Mean ± SD of fasting blood sugar, cholesterol, TG, ESR1, ESR2, and fibrinogen levels in the patient group was statistically more in the male patient group in relation to their sex-matched controls, but this was not seen for HDL or CRP. The female group showed a significant difference as regards fasting blood sugar and fibrinogen levels compared with their controls. [Table 3] and [Table 4].

Table 3: Comparison between the two studied groups according to investigational data

In this study, the mean serum level of total testosterone was not significantly higher (62.93 ± 19.24) however the mean SHBG was significantly lower (24.90 ± 14.60) in male patients compared with male controls. On the other hand this significance was not found in the female group, neither in the total number of patients [Table 5].

Table 5: Comparison between the two studied groups according to hormonal study in the male and female group

HOMA-IR serum level was significantly higher in both the male and the female group compared with their sex-matched controls [Table 5].

Discussion

Epidemiological studies as regards the association between AGA and CVD have produced varying results. Although some have shown an increase in cardiovascular risk, especially in early-onset alopecia, others have failed to confirm this observation [6].

In the current study, age, weight, height, smoking, diet, and drug intake were not significantly different in the patients with AGA and controls. However, there was a significantly higher prevalence of family history of CVD and family history of AGA in the male and female AGA groups than in controls. There was a highly significant relationship between the presence of a family history of AGA and a higher frequency of a family history of early CVD in the patients with AGA. A higher prevalence of MS (ATP-III criteria) was seen in this study in both male and female patients with AGA than in controls. This is in agreement with the findings of Selvador et al., who proved the prevalence of MS according to the ATP-III criteria in patients with AGA [13]. The relationship between CVD and MS is well documented. Some authors found that individuals who met ATP-III MS criteria had a 2.59-fold greater likelihood (odds ratio = 2.59) of a cardiovascular event in the next 10 years [14]. Abdominal obesity or waist circumference was recently defined as an essential criterion for the diagnosis of MS. In this study, a higher mean circumference was found in men and women with AGA than in sex-matched controls. However, the patients with AGA showed no differences compared with controls in weight or height. This is in agreement with the findings of Salvador et al. [13]. This indicates that patients with AGA undergo an abdominal redistribution of fat, which is considered an important cardiovascular risk factor. The prevalence of these cardiovascular risk factors slightly differs between male and female patients with AGA. This is in agreement with the findings of Matilanen et al.[15], whose study revealed that waist circumference was greater in women with extensive hair loss (Ludwig's grade II or III).

Mean systolic BP values were higher in male and female patients with AGA than in controls. Arias-Santiago et al.[16] also found higher BP in male patients with AGA compared with controls (65 vs. 45%). Ahouansou et al.[5] detected AGA in 82% of hypertensive patients versus 56% of normotensive men. Two explanations have been proposed for this association: one is that the androgens implicated in AGA bind with mineralocorticoid receptors, favoring BP increase, and the other is that hyperaldosteronism, which underlies most hypertension cases, directly participates in the development of alopecia.

In the current study we found a significant difference in testosterone values between the male patient and control groups only; therefore, the elevated BP values in patients with AGA would be attributed to an increase in peripheral sensitivity to androgens and also to the effect of testosterone effect.

In our study, TG and cholesterol levels were significantly elevated in male patients in relation to their sex-matched controls. Similarly, Sadighha and Zahed [17] recently confirmed that male patients with AGA have elevated TG levels. Similar results were reported by Matilainen et al.[18]. In contrast, in a study by Sharrett et al. [19], triglyceridemia was seen in men who had undergone revascularization as a result of heart disease and higher TG values and significantly lower HDL values were found in female patients with AGA but not in the male patients with AGA. Elevated TGs and low HDL levels are related to the transition from atheroma to atherothrombosis.

In our study, fasting blood sugar values were higher in patients with AGA than in controls; this was related to peripheral insulin resistance. Hirsso et al.[7] found that 21% of patients with AGA had diabetes compared with 12% of controls.

In the current study, total testosterone level was not significantly higher but SHBG was significantly lower in male patients in relation to their sex-matched controls. It is known that patients with AGA do not have higher androgen levels but rather a greater peripheral sensitivity to androgens. Testosterone is transformed by the action of 5a-reductase into DHT, acting on hair follicles and producing their miniaturization, and this mechanism is enhanced in patients with AGA. Lower SHBG gives more free testosterone that can exert its action at peripheral level [20], thus affecting cardiovascular risk. The 5a-reductase enzyme in the muscle layer of blood vessels and the heart [11] converts testosterone into DHT, stimulating synthesis of the smooth muscle of the vessels. The relationship between AGA and atheroma plaque may therefore be explained by a greater action of androgens in the scalp and in vascular muscle, favoring follicular miniaturization in one and atheroma plaque in the other.

In men with AGA, ESR1 and ESR2 values were significantly higher than that in male controls, but fibrinogen serum level was significantly higher in both male and female patients in relation to the sex-matched control groups. The previous parameters are called acute phase reactants and they have a role in acute inflammation. Chronic inflammation was found to play an important role in the development of insulin resistance, endothelial dysfunction, and CVD [21]. Possible proinflammatory situation underlying AGA shown by higher mean values of acute phase reactants may favor the increase in proinflammatory cytokines found in the arterial wall and hair follicle. Hence, the microinflammation found in the hair follicle, which may be implicated in the pathogeny of alopecia, could be the manifestation of a systemic inflammation that is related to the higher frequency of MS and CVD in patients with AGA [7].

HOMA-IR, which is an indicator for insulin resistance was found in this study to be increased in the patients with AGA in both the male and female groups; similar results were reported by Abdel Fattah and Darwish [22] in their study, and this might explain the relationship between AGA and CVD. High insulin levels are the central element of MS, favoring carbohydrate intolerance and central abdominal obesity. It has also been suggested that insulin favors vasoconstriction and nutritional deficit in scalp follicles, enhancing the effect of DHT on follicular miniaturization [3],[22]. Moreover, low circulating levels of SHBG are a strong predictor of the risk for type 2 diabetes and is associated with AGA, as we found in patients with AGA in this study and as proved by Ding et al.[23] in their study.

Conclusion

In the present study, AGA was significantly associated with an increased risk for CVD among both male and female patients, and the association was dependent on the severity of baldness. Clarifying the relationship between AGA and MS and cardiovascular risks may help in approaches to the early detection of heart disease, as it might permit the reliable identification of individuals with an increased risk for a cardiac event, thereby allowing the delivery of appropriate therapy (e.g. antihypertensive or lipid-lowering therapy) to improve the prognosis of such high-risk individuals. Finally, more studies with larger numbers of patients are required to confirm these findings and to analyze the pathogenic mechanisms underlying the increase in cardiovascular risk in patients with AGA.

National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106 :3143-3421.